Cyclic-adenosine monophosphate (cAMP) and cyclic-guanosine monophosphate (cGMP) are second messengers that regulate a vast array of cellular responses, particularly within the central nervous system. These cyclic nucleotides mediate biological response to extracellular signals (e.g., hormones, light, neurotransmitters) and influence processes such as ion channel function, muscle contraction, learning, differentiation, apoptosis, lipogenesis, glycogenolysis, gluconeogenesis, and proinflammatory mediator production and action (Kehler, J., Nielsen, J., Curr. Pharm. Des. 2011, 17, 137-150).
Phosphodiesterases (PDEs) are a family of enzymes that render cAMP and cGMP inactive through hydrolysis of the cyclic nucleotide 3′,5′-phosphodiester bond, and thus play a crucial role in controlling intracellular levels of cAMP/cGMP. Phosphodieasterase-10A (PDE10A), a dual-specificity phosphodiesterase, can convert both cAMP to AMP and cGMP to GMP (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K. et al. Eur. J. Biochem. 1999, 266, 1118-1127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A is primarily expressed in the brain in the medium spiny neurons of the striatum, nucleus accumbens, and olfactory tubercle (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Seeger, T. F. et al. Brain Research, 2003, 985, 113-126). These constitute the core of the basal ganglia system, which is involved in the regulation of motor, appetitive, and cognitive processes.
The activity of PDE10A can be modified or regulated by the administration of PDE10A inhibitors. PDE10A inhibitors have therapeutic potential for the treatment for disorders and conditions mediated in part by dysfunction of the basal ganglia, other parts of the central nervous system and other PDE10A expressing tissues. Such disorders and conditions include, but are not limited to, certain psychotic disorders such as schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder or substance-induced psychotic disorder, anxiety disorders such as panic disorder, obsessive-compulsive disorder, acute stress disorder or generalized anxiety disorder, obsessive/compulsive disorders, drug addictions, movement disorders such as Parkinson's disease or restless leg syndrome, cognition deficiency disorders such as Alzheimer's disease or multi-infarct dementia, mood disorders such as depression or bipolar disorders, or neuropsychiatric conditions such as psychosis, attention-deficit/hyperactivity disorder (ADHD) or related attentional disorders. PDE10A inhibitors are also suitable for the treatment of diabetes and related disorders such as obesity by regulating the cAMP signaling system. PDE10A inhibitors might also be useful in preventing neurons from undergoing apoptosis by raising cAMP and cGMP levels and, thus, might possess anti-inflammatory properties. Neurodegenerative disorders treatable with PDE10A inhibitors include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, stroke and spinal cord injury. The growth of cancer cells is inhibited by cAMP and cGMP. Thus by raising cAMP and cGMP, PDE10A inhibitors can also be used for the treatment of different solid tumors and hematological malignancies such as renal cell carcinoma or breast cancer.
Although various classes of compounds demonstrating PDE10A inhibitory activity exist, it would be beneficial to provide additional compounds demonstrating PDE10A modulation that can be incorporated into pharmaceutical compositions useful for therapeutic methods. A useful tool for assessing the ability of a compound to modulate a particular receptor in humans and animals is positron emission tomography (PET). Positron emission tomography includes the use of positron or gamma emitting radiolabeled compounds to study the interaction between an unlabeled compound and the radiolabeled compound for binding to the receptor of interest. This information is valuable for clinical candidate selection, determination of first-in-human dosing levels, proof of concept studies, and assessment of probability of success of a drug candidate relative to its therapeutic index. The topic and use of positron-emitting ligands for this purpose has been generally reviewed, for example in “PET ligands for assessing receptor occupancy in vivo” Burns, et al Annual Reports in Medicinal Chemistry (2001), 36, 267-276; “Ligand-receptor interactions as studied by PET: implications for drug development” by Jarmo Hietala, Annals of Medicine (Helsinki) (1999), 31(6), 438-443; “Positron emission tomography neuroreceptor imaging as a tool in drug discovery, research and development” Burns, et al. Current Opinion in Chemical Biology (1999), 3(4), 388-394.
Although compounds potentially useful as PDEA10 PET ligands are known, in general, these tracers suffer from high lipophilicity that can lead to poor specific/nonspecific binding ratios. Furthermore, the kinetics of these tracers and existence of significant quantities of brain-penetrant labeled metabolites may hinder their effectiveness for quantitatively evaluating enzyme occupancy in humans. Accordingly, it would be beneficial to provide additional compounds useful for noninvasive imaging of PDE10A receptor occupancy in humans and animals. In particular, it would be beneficial to provide PDEA10A PET ligands having optimal lipophilicity, protein binding, permeability glycoprotein (P-gp) interaction, free brain concentrations, specific/nonspecific binding ratios, and human hepatocyte metabolic stability.